Kidney growth in normal and diabetic mice is not affected by human insulin-like growth factor binding protein-1 administration

Insulin-like growth factor I (IGF-I) accumulates in the kidney following the onset of diabetes, initiating diabetic renal hypertrophy. Increased renal IGF-I protein content, which is not reflected in messenger RNA (mRNA) levels, suggests that renal IGF-I accumulation is due to sequestration of circulating IGF-I rather than to local synthesis. It has been suggested that IGF-I is trapped in the kidney by IGF binding protein 1 (IGFBP-1). We administered purified human IGFBP-1 (hIGFBP-1) to nondiabetic and diabetic mice as three daily sc injections for 14 days, starting 6 days after induction of streptozotocin diabetes when the animals were overtly diabetic. Markers of early diabetic renal changes (i.e., increased kidney weight, glomerular volume, and albuminuria) coincided with accumulation of renal cortical IGF-I despite decreased mRNA levels in 20-day diabetic mice. Human IGFBP-1 administration had no effect on increased kidney weight or albuminuria in early diabetes, although it abolished renal cortical IGF-I accumulation and glomerular hypertrophy in diabetic mice. Increased IGF-I levels in kidneys of normal mice receiving hIGFBP-1 were not reflected on kidney parameters. IGFBP-1 administration in diabetic mice had only minor effects on diabetic renal changes. Accordingly, these results did not support the hypothesis that IGFBP-1 plays a major role in early renal changes in diabetes

Dose-response effects of a new growth hormone receptor antagonist (B2036-PEG) on circulating, hepatic and renal expression of the growth hormone/insulin-like growth factor system in adult mice

The effects of growth hormone (GH) in regulating the expression of the hepatic and renal GH and insulin-like growth factor (IGF) system were studied by administering a novel GH receptor antagonist (GHRA) (B2036-PEG) at different doses (0, 1.25, 2.5, 5 and 10 mg/kg/day) to mice for 7 days. No differences were observed in the groups with respect to body weight, food consumption or blood glucose. However, a dose-dependent decrease was observed in circulating IGF-I levels and in hepatic and renal IGF-I levels at the highest doses. In contrast, in the 5 and 10 mg/kg/day GHRA groups, circulating and hepatic transcriptional IGF binding protein-3 (IGFBP-3) levels were not modified, likely resulting in a significantly decreased IGF-I/IGFBP-3 ratio. Hepatic GH receptor (GHR) and GH binding protein (GHBP) mRNA levels increased significantly in all GHRA dosage groups. Endogenous circulatory GH levels increased significantly in the 2.5 and 5 mg/kg/day GHRA groups. Remarkably, increased circulating IGFBP-4 and hepatic IGFBP-4 mRNA levels were observed in all GHRA administration groups. Renal GHR and GHBP mRNA levels were not modified by GHRA administration at the highest doses. Also, renal IGFBP-3 mRNA levels remained unchanged in most GHRA administration groups, whereas IGFBP-1, -4 and -5 mRNA levels were significantly increased in the 5 and 10 mg/kg/day GHRA administration groups. In conclusion, the effects of a specific GHR blockade on circulating, hepatic and renal GH/IGF axis reported here, may prove useful in the future clinical use of GHRAs

Osteoprotegerin and cardiovascular mortality in patients with non-ST elevation acute coronary syndromes

Objective: To assess the relationship between osteoprotegerin (OPG) and cardiovascular death, and the pathobiological mechanisms contributing to the association, in acute coronary syndromes (ACS). Design: Prospective observational. Setting: Biomarker substudy of MERLIN-TIMI 36, a randomised, placebo controlled trial of ranolazine in non-ST elevation (NSTE)-ACS. Patients: 4463 patients with NSTE-ACS. Interventions: Ranolazine or placebo. Main outcome measures: Incidence of cardiovascular death (CV death); additionally, heart failure (HF), cardiac arrhythmias, inhospital ischaemia, severe recurrent ischaemia or recurrent myocardial infarction (MI). Results: During a median follow-up of 341 days, 208 patients died of cardiovascular causes. The OPG baseline concentration was strongly associated with both 30 day and 1 year incidence of CV death. After adjustment for conventional risk markers, OPG concentrations (log transformed) remained a significant predictor of CV death by 30 days (HR (95% CI) 2.32 (1.30 to 4.17); p¼0.005) and by 1 year (HR 1.85 (1.33 to 2.59); p<0.001). Baseline levels of OPG were also an independent predictor of new or worsening HF at 30 days (HR 2.25 (1.38 to 3.69); p¼0.001) and 1 year (HR 1.81 (1.26 to 2.58) p¼0.001). By univariable analysis, higher OPG was associated with both early ischaemic and arrhythmic events. Although OPG levels were associated with recurrent MI within 12 months, this association was attenuated and no longer significant after multivariable adjustment. Conclusions: OPG is independently associated with 30 day and 1 year risk of cardiovascular mortality and HF development after NSTE-ACS. As no independent relationship between OPG levels and recurrent ischaemia or MI was observed, myocardial dysfunction may be a more important stimulus for OPG production than ischaemia in ACS

The effect of epidermal growth factor and IGF-I infusion on hepatic and renal expression of the IGF-system in adult female rats

Systemic administration of epidermal growth factor (EGF) in neonatal rats results in reduced body weight gain and decreased circulating levels of IGF-I, suggesting its involvement in EGF-induced growth retardation. We investigated the effect of EGF and/or IGF-I administration for 7 days on circulating IGF-I and IGFBP levels and hepatic and renal IGF-system mRNA expression profiles in adult female rats. EGF administration (30 microg/rat/day) did not influence body weight, liver or kidney weight. In contrast, IGF-I (400 microg/rat/day) and EGF/IGF-I administration increased both body weight and kidney weight. Also, serum IGF-I and the 30 kDa IGFBPs (IGFBP-1 and -2) were significantly increased in these groups. Serum IGFBP-3 levels increased in the IGF-I group along with increased hepatic IGFBP-1 and -3 mRNA levels. In contrast, in the EGF administration group serum IGFBP-3 levels were significantly decreased; however, the mRNA levels remained unchanged. In the EGF/IGF-I administration group, serum IGF-I and IGFBP-3 levels were significantly lowered when compared with the IGF-I administration group. This was in contrast to the effect on kidney weight increase that was identical for the IGF-I and EGF/IGF-I groups. The decrease in serum IGFBP-3 was not reflected at the hepatic IGFBP-3 mRNA level. IGFBP-3 expression might be regulated at a post-transcriptional level although EGF induced IGFBP-3 proteolysis could not be demonstrated in vitro. We conclude that EGF administration reduced serum IGFBP-3 whereas IGF-I administration increased the level of IGFBP-3 and IGF-I and resulted in an increased body and kidney weight in adult female rats

The role of the IGF axis in IGFBP-1 and IGF-I induced renal enlargement in Snell dwarf mice

Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) is generally believed to inhibit IGF action in the circulation. In contrast, IGFBP-1 has been reported to interact with cell surfaces and enhance IGF-I action locally in some tissues. Renal IGFBP-1 levels are found elevated in various conditions characterized by renal growth (e.g. diabetes mellitus, hypokalemia). To test whether IGFBP-1 is a renotropic factor, IGFBP-1 was administered alone or in combination with IGF-I to Snell dwarf mice, an in vivo model without compensatory feedback effects on growth hormone (GH) secretion. In three control groups of Snell dwarf mice, placebo, GH or IGF-I was administered. Compared with placebo, kidney weight increased in all treated groups, however, with different effects on kidney morphology. Administration of IGF-I, alone or in combination with IGFBP-1, tended to increase glomerular volume, while no changes were seen in the other groups. Administration of IGFBP-1 or IGFBP-1+IGF-I both caused dilatation of the thin limbs of Henle's loop, while GH or IGF-I administration had no visible effect. Furthermore, IGF-I administration resulted in an increased mean number of nuclei per cortical area and renal weight, whereas GH, IGF-I+IGFBP-1 or IGFBP-1 caused a decreased renal nuclei number. In situ hybridization and immunohistochemistry showed specific changes of the renal IGF system expression patterns in the different groups. Particularly, IGFBP-1 administration resulted in extensive changes in the mRNA expression of the renal IGF system, whereas the other administration regimen resulted in less prominent modifications. In contrast, administration of IGFBP-1 and IGFBP-1+IGF-I resulted in identical changes in the protein expression of the renal IGF system. Our results indicate that IGFBP-1, alone or in combination with IGF-I, demonstrated effects on the renal tubular system that differ from the effects of IGF-I

Antioxidant treatment attenuates lactate production in diabetic nephropathy

The early progression of diabetic nephropathy is notoriously difficult to detect and quantify before the occurrence of substantial histological damage. Recently, hyperpolarized [1-13C]pyruvate has demonstrated increased lactate production in the kidney early after the onset of diabetes, implying increased lactate dehydrogenase activity as a consequence of increased nicotinamide adenine dinucleotide substrate availability due to upregulation of the polyol pathway, i.e., pseudohypoxia. In this study, we investigated the role of oxidative stress in mediating these metabolic alterations using state-of-the-art hyperpolarized magnetic resonance (MR) imaging. Ten-week-old female Wistar rats were randomly divided into three groups: healthy controls, untreated diabetic (streptozotocin treatment to induce insulinopenic diabetes), and diabetic, receiving chronic antioxidant treatment with TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) via the drinking water. Examinations were performed 2, 3, and 4 wk after the induction of diabetes by using a 3T Clinical MR system equipped with a dual tuned 13C/1H-volume rat coil. The rats received intravenous hyperpolarized [1-13C]pyruvate and were imaged using a slice-selective 13C-IDEAL spiral sequence. Untreated diabetic rats showed increased renal lactate production compared with that shown by the controls. However, chronic TEMPOL treatment significantly attenuated diabetes-induced lactate production. No significant effects of diabetes or TEMPOL were observed on [13C]alanine levels, indicating an intact glucose-alanine cycle, or [13C]bicarbonate, indicating normal flux through the Krebs cycle. In conclusion, this study demonstrates that diabetes-induced pseudohypoxia, as indicated by an increased lactate-to-pyruvate ratio, is significantly attenuated by antioxidant treatment. This demonstrates a pivotal role of oxidative stress in renal metabolic alterations occurring in early diabetes. </jats:p

Thyroid function in Danish greenhouse workers

BACKGROUND: From animal studies it is known that currently used pesticides can disturb thyroid function. METHODS: In the present study we investigated the thyroid function in 122 Danish greenhouse workers, to evaluate if greenhouse workers classified as highly exposed to pesticides experiences altered thyroid levels compared to greenhouse workers with lower exposure. Serum samples from the greenhouse workers were sampled both in the spring and the fall to evaluate if differences in pesticide use between seasons resulted in altered thyroid hormone levels. RESULTS: We found a moderate reduction of free thyroxine (FT4) (10–16%) among the persons working in greenhouses with a high spraying load both in samples collected in the spring and the fall, but none of the other measured thyroid hormones differed significantly between exposure groups in the cross-sectional comparisons. However, in longitudinal analysis of the individual thyroid hormone level between the spring and the fall, more pronounced differences where found with on average 32% higher thyroid stimulating hormone (TSH) level in the spring compared to the fall and at the same time a 5–9% lower total triiodthyroxin (TT3), free triiodthyroxine (FT3) and FT4. The difference between seasons was not consistently more pronounced in the group classified as high exposure compared to the low exposure groups. CONCLUSION: The present study indicates that pesticide exposure among Danish greenhouse workers results in only minor disturbances of thyroid hormone levels

Plasma neutrophil gelatinase associated lipocalin (NGAL) is associated with kidney function in uraemic patients before and after kidney transplantation

<p>Abstract</p> <p>Background</p> <p>Neutrophil gelatinase associated lipocalin (NGAL) is a biomarker of kidney injury. We examined plasma levels of NGAL in a cohort of 57 kidney allograft recipients (Tx group, 39 ± 13 years), a uraemic group of 40 patients remaining on the waiting list (47 ± 11 years) and a control group of 14 healthy subjects matched for age, sex and body mass index (BMI). The kidney graft recipients were studied at baseline before transplantation and 3 and 12 months after transplantation and the uraemic group at baseline and after 12 months.</p> <p>Methods</p> <p>NGAL was measured using a validated in-house Time-Resolved Immuno-flourometric assay (TRIFMA). Repeated measurements differed by < 10% and mean values were used for statistical analyses. Spearman rank order correlation analysis and the Kruskal-Wallis non-parametric test were used to evaluate the association of NGAL concentrations with clinical parameters.</p> <p>Results</p> <p>Plasma NGAL levels before transplantation in the Tx and uraemic groups were significantly higher than in the healthy controls (1,251 μg/L, 1,478 μg/L vs. 163 μg/L, p < 0.0001). In the Tx group NGAL concentrations were associated with serum creatinine (R = 0.51, p < 0.0001), duration of end-stage renal failure (R = 0.41, p = 0.002) and leukocyte count (R = 0.29, p < 0.026). At 3 and 12 months plasma NGAL concentrations declined to 223 μg/L and 243 μg/L, respectively and were associated with homocysteine (R = 0.39, p = 0.0051 and R = 0.47, p = 0.0007).</p> <p>Conclusions</p> <p>Plasma NGAL is a novel marker of kidney function, which correlates to duration of end-stage renal failure (ESRD) and serum creatinine in uraemic patients awaiting kidney transplantation. Plasma NGAL is associated with homocysteine in transplanted patients. The prognostic value of these findings requires further studies.</p